TLR4-MEDIATED EPIGENETIC AND SENESCENCE MECHANISMS IN EMPHYSEMA

TLR4 介导的肺气肿表观遗传和衰老机制

• 批准号: 9981929
• 负责人: PATTY J LEE
• 金额: $ 32.68万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981929
• 关键词: Age; Aging; Alveolar; Antioxidants; CDKN2A gene; Cause of Death; Cell Survival; Cells; Cellular Structures; Chronic Obstructive Airway Disease; Chronic lung disease; DNA; DNA Modification Methylases; DNA Modification Process; DNMT3a; Data; Development; Elderly; Endothelial Cells; Enzymes; Epigenetic Process; Epithelium; Exhibits; Experimental Models; Future; Gases; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; HDAC2 gene; Histones; Human; Immune; Immune system; Immunologic Receptors; Impairment; Infection; Inflammatory; Inhalation; Injury; Knock-in Mouse; Knockout Mice; Life; Link; Longevity; Luciferases; Lung; Lung Capacity; Lung diseases; Maintenance; Mediating; Methylation; Molecular; Molecular Target; Mus; Natural Immunity; Outcome; Pathway interactions; Post-Translational Protein Processing; Predisposition; Prevention; Process; Proteins; Pulmonary Emphysema; Recording of previous events; Regulation; Reporting; Risk Factors; Role; Source; Structure; TLR4 gene; Testing; Tetanus Helper Peptide; Therapeutic; Toxic Environmental Substances; Toxin; adaptive immune response; age related; aged; antimicrobial; cell type; cigarette smoke; cigarette smoking; clinically relevant; design; effective therapy; exposed human population; exposure to cigarette smoke; histone deacetylase 2; in vivo; inflammatory marker; innovation; insight; mortality; mouse toll-like receptor 4; new therapeutic target; novel; oxidant stress; prevent; response; senescence; stressor

PROJECT SUMMARY COPD is now the 3rd leading cause of death worldwide. Emphysema, characterized by airspace enlargement and impaired gas exchange, is a major subtype of COPD. The cumulative effects of cigarette smoke exposure (CS) and environmental toxins across the lifespan are important contributing factors to the development of emphysema. Yet very little is known about the underlying mechanisms, which limits therapies. Our overall goals are to understand the molecular mechanisms of how our lungs maintain normal structural integrity and how they protect against inhaled toxins, such as CS. We identified a critical role for an innate immune receptor, Toll-like receptor 4 (TLR4), in lung maintenance and in preventing inappropriate activation of aging and injury pathways. Unfortunately, age and CS, two of the most common risk factors for COPD, result in inadequate levels of TLR4, thus predisposing to emphysema. Our studies will fill current gaps in our understanding of how the immune system, in specific lung cells, can impact lung-protective responses even in the absence of infection, thereby offering potential new therapeutic targets. Using TLR4-deficiency and CS as clinically relevant experimental models of emphysema, we identified mechanistic roles for the senescence molecule, p16INK4A, and DNA-modifying enzymes, HDAC2, Dnmt3a and Tet2, in emphysema. In addition, we offer the first in vivo evidence that increased p16INK4A contributes to emphysema. Our overall hypothesis is that structural cell TLR4 is required to maintain normal lung integrity, at baseline and after CS, by inhibiting p16INK4A via HDAC2-Dnmt3a-Tet2-mediated mechanisms. We will use a combination of age- and CS- exposed human and mouse lungs/cells as well as innovative gene manipulations to test this hypothesis in the following Aims: 1) Identify mechanisms of decreased TLR4 expression with aging and CS and the contribution of TLR4 in specific structural cells to emphysema. 2) Determine the mechanisms of decreased HDAC2 in TLR4-deficient and CS-exposed cells. 3) Identify HDAC2 and Dnmt3a / Tet2 -mediated mechanisms of p16INK4A induction and the contribution of p16INK4A in specific structural cells to emphysema. Our studies will expand our basic understanding of the molecular drivers of emphysema, establish previously unrecognized interactions amongst innate immunity, senescence and DNA modifications and inform future preventative or therapeutic approaches to a range of age- and CS-related lung diseases.

项目摘要 COPD现在是全球死亡的第三大原因。肺气肿，以空域扩大为特征 气体交换受损是COPD的主要亚型。香烟烟雾暴露的累积影响 （CS）和整个生命周期的环境毒素是发展的重要因素 气肿。然而，关于限制疗法的基本机制知之甚少。我们的整体 目标是了解我们的肺如何保持正常结构完整性和 它们如何防止吸入的毒素，例如CS。我们确定了先天免疫受体的关键作用， Toll样受体4（TLR4），在肺部维持和防止衰老不适当激活时 途径。不幸的是，年龄和CS是COPD的两个最常见的风险因素，导致不足 TLR4的水平，因此倾向于肺气肿。我们的研究将填补我们对如何理解的差距 在特定的肺部细胞中，免疫系统即使在没有的情况下也会影响肺部保护反应 感染，从而提供潜在的新治疗靶标。使用TLR4缺乏效率和CS作为临床 相关的肺气肿实验模型，我们确定了衰老分子的机械作用， P16INK4A和DNA修饰酶，HDAC2，DNMT3A和TET2，在肺气肿中。此外，我们提供 首先，体内证据表明P16INK4A增加会导致肺气肿。我们的总体假设是 在基线和CS之后，需要结构性细胞TLR4来维持正常的肺完整性，通过抑制 P16INK4A通过HDAC2-DNMT3A-TET2介导的机制。我们将结合年龄和CS- 暴露于人类和小鼠肺/细胞以及创新的基因操纵，以检验该假设 以下目的：1）确定随着衰老和CS的降低TLR4表达的机制以及 特定结构细胞中TLR4对肺气肿的贡献。 2）确定减少的机制 TLR4缺陷型和CS暴露细胞中的HDAC2。 3）识别HDAC2和DNMT3A / TET2介导的机制 P16INK4A诱导和特定结构细胞中p16Ink4a对肺气肿的贡献。我们的研究将 扩展我们对肺气肿的分子驱动因素的基本理解，建立先前未知的 先天免疫，衰老和DNA修改之间的相互作用，并为未来的预防措施提供信息 针对一系列年龄和CS相关的肺部疾病的治疗方法。